Colorectal cancer (CRC) is one of the leading causes of cancer mortality worldwide. In the last decade, median overall survival has increased significantly with the introduction of new cytotoxics and biologic therapies. Notably, the definition of molecular markers predicting benefit with epidermal growth factor receptor (EGFR)-targeted agents has led to important advances in the personalized treatment of CRC. Data derived from multiple phase III trials have indicated that KRAS mutations can be considered a highly specific negative biomarker of response to anti-EGFR monoclonal antibodies. The predictive value of additional mutations and deregulations of the signaling pathways downstream of the EGFR such as BRAF, NRAS, PIK3CA, or PTEN is under intensive investigation. In addition, status of microsatellite instability and molecular markers related to the metabolism of chemotherapy agents has shown promising ability to select patients with higher chances of response to cytotoxic agents. Although attempts to identify predictive factors for efficacy to antiangiogenic therapies have been disappointing, further research on this field will maximize their therapeutic index. Determination of molecular predictive factors before selection of chemotherapy is rapidly approaching us to the paradigm of individualized treatment of CRC.